[78] Results from genetic studies in mice and rats have demonstrated that knockout or mRNA interference of DDAH-1 is associated with an increase in ADMA and leads to a cardiovascular phenotype, that is, hypertension, consistent with NOs inhibition.[79] In humans it was found that the plasma levels of ADMA are associated with mean blood pressure levels in healthy subjects.[72] Increased ADMA concentration was also observed in humans with essential hypertension compared to normotensive healthy subjects.[80] Infusion of endogenous ADMA in healthy volunteers with a concomitant increase of serum ADMA

concentration from 0.95 μmol/L to 23 μmol/L was necessary to affect systemic BP.[81] Also, it caused significant Ivacaftor supplier decrease in renal sodium excretion, significant decrease in effective renal plasma flow (ERPF) and significant increase in renovascular resistance (RVR).[81] Increased ADMA has been observed in patients with white-coat hypertension.[82] The possible mechanisms by which endogenous ADMA is involved in the pathogenesis of hypertension are: (i) The decrease of renal NO, by ADMA and the increase of O2− can lead to a pathological reabsorption of NaCl and H2O (even with subpressor dose of ADMA[83]), resulting in hypertension.[78, 84] (ii) ADMA can cause vasoconstriction

and increase of blood pressure; it impairs the endothelial-dependent relaxation GDC-0941 cell line C59 molecular weight and increases the adhesion ability of endothelial cell.[66, 85] (iii) Moreover, the intraglomerularhaemodynamic state is disturbed, the tubular glomerular retrograde

regulation and the renal adaptation to sympathetic activity are both impaired (sympathetic overactivity).[86] (iv) Shear stress increases PRMT expression and activity and stimulates production of ADMA in cultured endothelial cells.[39] Shear stress may contribute to the increase in ADMA observed in hypervolaemic states such as high-salt diet.[87] It seems that higher ADMA levels can ‘produce’ hypertension and on the other hand maybe present secondarily in hypertension as a response to shear stress. Proteinuria, even microalbuminuria, is a traditional progression factor of kidney damage with or without diabetes or hypertension.[9] There is an increasing body of evidence that endothelial dysfunction is linked to proteinuria.[88, 89] Impaired NO production is the characteristic feature of endothelial dysfunction and ADMA levels were related with proteinuria.[11, 90] Indeed there is a reference for an ADMA dose-related damage of the glomerular barrier, as well as increased permeability to albumin resulting in proteinuria in an in vitro experimental model (isolated glomeruli). The ADMA concentrations applied were similar to the circulating ADMA concentration in CKD patients.